Improving drug selectivity for target tissue is an established goal in the medical arts. In general, it is desirable to deliver a drug selectively to its target, so that dosage and, consequently, side effects can be reduced. This is particularly the case for toxic agents such as anticancer agents because achieving therapeutic doses effective for treating the cancer is often limited by the toxic side effects of the anticancer agent on normal, healthy tissue.
Extensive research has been done on the use of fatty acids as agents that improve selectivity of drugs for their target tissues. Fatty acids previously have been conjugated with drugs to help the drugs as conjugates cross the blood brain barrier. DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranched fatty acid that previously has been shown to be unusually effective, when conjugated to a drug, in crossing the blood brain barrier. DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic (lipophilic). The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.
Another example of the conjugation of fatty acids to a drug is the attachment of pipotiazine to stearic acid, palmitic acid, enanthic acid, undecylenic acid or 2,2-dimethyl-palmitic acid. Pipotiazine is a drug that acts within the central nervous system. The purpose of conjugating pipotiazine to the fatty acids was to create an oily solution of the drug as a liquid implant for slow release of the drug when injected intramuscularly. The release of the drug appeared to depend on the particular fatty acid selected, and the drug was tested for its activity in the central nervous system.
Lipidic molecules, including fatty acids, also have been conjugated with drugs to render the conjugates more lipophilic than the unconjugated drugs. In general, increased lipophilicity has been suggested as a mechanism for enhancing intestinal uptake of drugs into the lymphatic system, thereby enhancing the entry of the conjugate into the brain and also thereby avoiding first-pass metabolism of the conjugate in the liver. The type of lipidic molecules employed have included phospholipids, non-naturally occurring branched and unbranched fatty acids, and naturally occurring branched and unbranched fatty acids ranging from as few as 4 carbon atoms to more than 30 carbon atoms. In one instance, enhanced receptor binding activity was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with the phospholipid membrane to act as a distal anchor for the receptor ligand in the membrane micro environment of the receptor. This increase in potency, however, was not observed when the same lipid derivatives of adenosine receptor antagonists were used, and generalizations thus were not made possible by those studies.
Of key importance in the treatment of cancer, viruses, and psychiatric illness is the selectivity and targeting of drugs to tissues. The increased targeting reduces the amount of pharmaceutical agents needed, and the frequency of administration of the pharmaceutical agents, both features especially important in treatments that involve administration of pharmaceutical agents that may be toxic to surrounding tissues and may cause side effects. Because of the critical importance of effective treatments for cancer, viral diseases and psychiatric disorders and the difficulty in selectively targeting the affected tissues, there is presently a need for effective methods to target tissues with powerful drugs, while also reducing the side effects and difficult administration regimens.
Fatty amines are lipidic molecules terminating in an amino group (unlike fatty acids, which, of course, terminate in a carboxylic acid group). Unlike fatty acids, fatty amines are not a prevalent tissue component of mammals. They typically are prepared synthetically using fatty acids as a starting material.